Abstract
Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype–phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype–phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re-sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype–phenotype correlation of the disease.
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Acknowledgements
We thank Dr Giulia Bisogno for her clinical support in the results interpretation. We acknowledge the GTEx Project and their funding agencies to have made their data publically available. The present study was supported by an Investigator-Initiated Research to the University of Rome ‘Tor Vergata’ from Pfizer Inc. Pfizer Inc. had no role in the study design, data analysis, and results interpretation of the present study.
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RP had full access to all study data and take responsibility for the integrity of the data and the accuracy of the analyses.
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ML received travel grants from Kedrion, Pfizer, and Grifols. The other authors declare no conflict of interest.
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Iorio, A., De Lillo, A., De Angelis, F. et al. Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis. Eur J Hum Genet 25, 1055–1060 (2017). https://doi.org/10.1038/ejhg.2017.95
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DOI: https://doi.org/10.1038/ejhg.2017.95
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